Disclosed herein are compositions and processes for the preparation and use of thyroid hormone derivatives as active pharmaceutical ingredients (APIs) for pharmaceutical compositions. These thyroid hormone derivatives are prepared as their organic acid addition salts which exhibit improved stability compared to the parent compound(s). The instability of the thyroid hormones (of synthetic or animal origin) due to labile aromatic iodine substitution (or other factors) has created formulation, storage and dosing problems for the commercial formulated drug product. The organic acid addition salts described herein exhibit improved stability and handling properties which overcome the existing deficiencies.
Each of the thyroid hormones and related compounds are known by a variety of names ranging from approved International Union of Pure and Applied Chemist (IUPAC) nomenclature to abbreviated naming to facilitate communication. For instance, 3,3′,5-triiodothyronine is known as liothyronine, or as T3. Similarly, 3,3′5,5′-tetraiodothyroxine is known as levothyroxine, or as T4. Further, each of these names may be preceded by the appropriate stereochemical indicator for the chiral center contained within the amino acid moiety on each compound. In commerce, the thyroid hormones are most often offered as their alkali metal salt, for instance levothyroxine sodium. These names are not intended to limit the concepts or the scope of the invention presented herein and a more complete listing of names for the thyroid hormones can be found in the Merck Index, 11th Edition under the headings of Liothyronine and under Levothyroxine Sodium. The descriptions herein may use these and other appropriate names interchangeably for each of the thyroid hormones.
Many active pharmaceutical ingredients (APIs) exhibit poor storage stability characteristics due to their chemical or physical response to heat, light, pH, or to oxidative conditions. Further, it is generally recognized that the particular stability profile of a pure API is an intrinsic property of that substance. It is a practical matter that the stability profile of an API be understood, documented and routinely tested on selected manufacturing batches to confirm the process is producing the API with the expected stability profile. The importance of a predictable stability profile, under acceptable storage conditions, cannot be overemphasized when the API will be used in humans. The lack of storage stability and the API's response to degradation stimulators can lead to the lack of drug efficacy, incorrect or ineffective dosage, and undesired, or even deleterious side-effects resulting from impurities generated by degradation pathways. Hence, the determination of a drug substance's stability profile is a well-recognized requirement in the pharmaceutical industry and stability testing is conducted on the API and on the final drug product as the finished dosage form.
Herein a number of terms are used to describe different aspects involved in preparing or establishing the stability of a drug substance and drug product. What is meant by a drug substance is: a molecular entity or compound, also known as an active pharmaceutical ingredient (API) that exhibits biological activity for the purpose of providing human or animal medication to treat disease, pain or any medically diagnosed condition. It is possible for a drug substance to be used in combination with one or more different drug substances to ultimately impart a biological response in humans or animals. A drug substance is typically formulated with other, non-biologically active compounds to provide a means of predictable and quantitative dosage delivery, or perhaps to impart acceptable stability features to the drug product. What is meant by a drug product is: a formulation, mixture or admixture of the drug substance with combinations of excipients, processing aids, buffers and perhaps other inert ingredients that allow delivery of the drug substance by the selected delivery mechanism to the patient at a predictable dosage. Various delivery mechanisms include solid oral dosage, for example, pills, tablets, or capsules. Additional delivery systems can include solution or suspension injection dosage forms (including depo drug products), transdermal patches, and nasal or inhalation devices. The dosage is the actual concentration delivered to the patient, and depending upon many factors and the actual delivery system selected, the dosage may be available for essentially immediate release, release over time, or manipulated by additional means for stimulated release (for example, by irradiation).
The stability profile exhibited by the drug substance in a bulk form and its stability when incorporated into a drug product should be demonstrated and understood. What is meant by the drug substance stability profile is: the analytical evidence of degradation of the drug substance to diminish its assay (and hence, to generate degradation impurities) as the drug substance is exposed over time to degradation stimuli. The analytical testing to determine or confirm the stability profile of the drug substance is routinely conducted on the bulk drug substance and approximately, simultaneously on the drug product containing the drug substance as these entities are subjected to the stability testing regimen. What is meant by stability testing is: the individual storage of the drug product and the drug substance in environmentally controlled chambers maintained at specific humidity and temperature conditions whereby samples of the stored materials can be removed at regular or predetermined intervals, with the samples to be subjected to analytical testing. The results from the analytical testing provide the stability profile of the drug substance and drug product as a function of time and storage conditions. From this data, an expiry date, or shelf-life can be determined such that formulation of drug products with the drug substance can provide commercial products having efficacious and predictable dosage forms eliciting the desired biological response.
For further background, stability testing for a drug substance is often separated into two activities. The first is an investigation to determine the chemical degradation pathway initiated by heat, light, pH or oxidative conditions. Experiments are conducted known as forced degradation studies to intentionally degrade or decompose the drug substance to a sufficient extent that degradation impurities can be assessed by analytical chemical methodology and to demonstrate that the impurities thus generated do not interfere with the quantitative assessment of the remaining, unaltered drug substance. The second activity relies on the results from the degradation investigation and consists of applying standardized exposure conditions adopted by the United States Food and Drug Administration and generally, universally applied to the commercial manufacture of drug substances and drug products. In most instances, the materials (drug substance and product) are subjected to two stability chamber storage conditions to reflect 1) a reasonable temperature and humidity exposure and 2) a more aggressive exposure known as accelerated stability testing. On occasion, a third storage condition at low temperature (approximately 5° C.) is conducted for what is termed pharmaceutical elegance, however this condition provides little meaningful or practical information in most cases. The period of exposure for the reasonable or representative storage condition is used to establish the expiry dating (usually years); the aggressive storage condition is most often a shorter period (months) and can be used as an early warning indicator to potential instability issues. It is noteworthy to state the samples placed into stability storage chambers are packaged identically, as practicably possible, as the enclosure or container device used for the bulk drug substance or the final packaged drug product.
There are other factors that affect the stability of pharmaceutical materials, meaning drug substances or drug products. While it is generally recognized that the stability profile of a pure drug substance is a predictable property of the pharmaceutical material, the overall stability of a molecular entity, compound or drug substance or any formulation with the drug substance, may be impacted by other physical or chemical behavior the drug substance possesses. In this case, pure is defined by comparison to its manufacturing specifications and an assessment by appropriate analytical test procedures using a highly characterized and purified sample as a standard of comparison. The ability to modify these behaviors allows for improvements to the stability profile obtained.
As mentioned above, the forced degradation studies expose the drug substance to heat, light, high and low pH, and oxidative conditions. Often, these studies provide insight into physical or chemical modifications of the drug substance that will improve the stability of the compound. “Martin's Physical Pharmacy and Pharmaceutical Sciences”, 5th Edition, (Lippincott, Williams & Wilkins publisher); ©2006 authored by Patrick J. Sinko, on page 358 defines pharmacokinetics and pharmacodynamics. Pharmacokinetics is the mathematics of the time course of absorption, distribution, metabolism and excretion (ADME) of drugs in the body. The biologic, physiologic, and physicochemical factors that influence the transfer of those drugs in the body also influence the rate and extent of ADME of those drugs in the body. In many cases, the pharmacologic action and the toxicologic action are related to the plasma concentration of drugs. Through the study and application of pharmacokinetics, the pharmacist can individualize therapy for the patient. Pharmacodynamics is the study of the biochemical physiological effects of drugs and their mechanisms of action. To illustrate this concept, the physical form of the drug substance, perhaps in a solid oral dose application, may determine the pharmacokinetic (PK) profile of the drug substance when used as a drug product in humans or animals. As an example, a drug substance's crystal structure or polymorphic form may impact the bioavailability of the material to the patient. In this case, a manufacturing process may be developed to yield a single crystal form or polymorph providing a predictable PK profile and indeed, it is not unusual that one (or more) polymorphs of a drug substance exhibit an enhanced stability profile compared to other available polymorphs of the identical drug substance. This is an example of manipulating physical properties of the drug substance to provide improved stability characteristics of the active pharmaceutical ingredient and likely, of the commercial pharmaceutical drug product. Similarly, chemical modifications can be implemented that favorably impact the stability profile also. As an example, many hydrochloride or mineral acid salts of drug substances are hydroscopic (also defined as hygroscopic). In this case, the ionic nature of the drug substance (as a salt) may diminish its own stability profile by a host of mechanisms, but for simplicity, the drug substance may have a propensity to absorb water. The water, absorbed from the environment (packaging materials, exposure to air, or in the case of formulated products, from other materials), may lead to degradation products. Hence, the aforementioned description of stability chamber testing at specific temperature and humidity conditions reflects this concern for water leading to degradation products and perhaps, an unacceptable stability profile for the drug substance. A possible chemical modification could include selection of a salt form that does not exhibit hygroscopic properties. Like the previous physical property modification example, changing the salt form may alter the drug substance's PK profile.
Careful attention must be applied such that improving one parameter, such as a drug substance's stability profile, does not adversely alter the desired efficacy when used in a drug product. More specifically, a drug substance's salt form may impact the drug's bioavailability (the rate and location of release, and steady-state concentration) in the body.
As a further illustration of improving a drug substance's stability profile, the selection of a given salt form may eliminate a specific degradation pathway. For instance, some degradation mechanisms are promoted by strong acid conditions, so a drug substance existing as a mineral acid salt may be intrinsically less stable than its weak acid analog. Without adhering to any specific theory or principle, a compound's decomposition as a hydrochloride may be greater than when compared to its decomposition as a citric acid salt and perhaps can be correlated to the relative strength (pKa) of each acid where citric acid is much weaker than hydrochloric acid. The combined effects of acid availability (and strength) through the drug substance's salt form and of the relative propensity of each salt form to absorb water may further delineate which salt form has the preferred stability profile. Consequently, the physical and/or chemical modification of a drug substance may improve its stability profile when subjected to forced degradation studies. However, these improvements, for commercial purposes, should be demonstrated under standardized stability chamber testing at regulated temperature and humidity.
The stability chamber testing serves an additional purpose by evaluating the impact the manufacturing process may have on the stability profile of a given batch of drug substance or drug product. In reality, drug substances and products are manufactured to specifications that represent the best-case scenarios for providing large quantities of acceptable pharmaceutical products to the world's population. Each batch of drug substance is analytically tested for adherence to each specification and is compared to a small, but highly characterized and purified sample of the drug substance known as an analytical standard. This initial testing represents the immediate (non-aged) comparison of the large production batch to the best available material—the analytical standard. Hence, the question arises as to how the manufacturing batch compares to the standard as time passes under given storage conditions. The production batch may contain trace amounts of materials that promote degradation that the analytical standard does not possess. Such trace materials may include intermediates along the synthetic pathway to the drug substance, residual solvents used in the synthesis, or minute traces of metals originating from the actual processing equipment. Individually, or together, these trace amounts of materials may promote the degradation of the drug substance to the extent the stability profile is unacceptable and/or a desired expiry date cannot be attained.
Stability testing, particularly accelerated stability testing is a means to quickly ascertain an API's degradation behavior by a kinetic plot of the assay, impurities and/or degradation impurities as a function of time under the cited conditions. Naturally, the stability profile of an API may be somewhat different when stored as the bulk material under conditions representing a less than optimum controlled environment. For instance, during normal commercial operations an API undergoes various inventory and logistical operations including warehouse storage, shipping and transport, sampling, and the like, wherein excursions from the standardized and laboratory controlled stability testing regimens may occur. During these excursions, the disposition of the API as being fit for use can be called into question. This typically results in analytical re-testing to assure the material it still meets the acceptance specifications. In addition, an understanding of the API's response to real-time storage stability conditions may mitigate or eliminate any potential concerns. Real-time storage stability conditions are defined as storage of the API (or drug product) over an extended period, usually at least one year and perhaps not longer than five years. The storage and handling of the API may be as a bulk sample (e.g. large carton or drum) or a smaller sample representative of the bulk packaging and subjected to the inventory exposure/excursion conditions the bulk API may undergo. A typical example of an exposure condition bulk API may experience is a container being partially used during manufacture of the final dose product. In this scenario, bulk API is exposed to an environment (perhaps a controlled environment), but it is then re-sealed and returned to inventory. Another common environmental exposure of bulk API occurs during routine removal of an analytical test sample from the bulk material. Real-time stability storage information provides business and technical management with insight into how to best manage the bulk API for its long-term stability and efficacy when formulated into a drug product. For drug products employing particularly low dosages of the API, such as the thyroid hormones, an understanding of the API's real-time storage stability assists in assuring the correct amount of the API is obtained in the dosage presentation. Real-time storage stability also allows for insight into how quickly, and under what conditions, drug product manufacturing must occur to assure the correct dosage is obtained in the drug product. Consequently, laboratory samples and API lot retains provide meaningful technical information to assess API stability under a host of conditions for which commercial bulk API may be exposed.
Practically, pamoic acid has received very little attention either by pharmaceutical scientists or synthetic organic chemists. Two simplistic observations are recurring themes in the folklore (i.e. industry practice or belief) surrounding pamoic acid derivatives. In general, the preparation of a pamoate salt converts a liquid material to a solid and an improved organoleptic property has been ascribed to such salts. Organoleptic properties, for example, are smell and taste, and pamoate salts of drug substances have been suggested as eliminating the bitter taste compared with other salts (or free base) of the drug substance.
The ability to form salts is a technique routinely employed by the practicing organic chemist. The methodology is used to separate and purify materials since many active pharmaceutical ingredients can be isolated and recrystallized as their salt with a concomitant improvement to their stability profile. It is a matter of in-depth experimentation, particularly for pharmaceutical materials, to identify which salt will optimize a complex set of variables. The salt selected may impact the drug substance's synthesis, synthesis yield, and the ability to purify the drug substance. The salt prepared will have intrinsic physical and chemical properties that impact its stability profile, pharmacokinetic behavior, formulation stability, ease of manufacturing into a final dose drug product (for instance the ability to obtain blend uniformity, or a tablet stable to mechanical manipulations), bioavailability, solubility and its basic efficacy and therapeutic selectivity. Individually or in combination inventive solutions are required, since a priori predictions to these considerations or to secondary influences such as the salt's steric bulk, relative pKa and pKb of the acid and base components respectively, the degree of association between the acid and base components (for example the use of acid or base components that are bi-, or multiple-dentate and have the ability to form tight complexes with its conjugate) are insufficient to guarantee a desired outcome. Truly, the factors are too numerous to successfully predict an outcome independent of experimental data.
While salt formation is a routinely practiced technique, the selection or identification of which salt to prepare requires a rigorous inventive contribution to obtain a material meeting a complex set of requirements. These requirements, as alluded to previously include an entire chain of events that begins with drug substance manufacturing (synthesis, isolation, purification and characterization), drug product formulation and manufacturing (appropriate for the desired delivery system or device), demonstration of the actual therapeutic value, and the event chain never completely ends because of an on-going stability testing program long after all the drug product has entered the marketplace. As a first approach to meeting this barrage of requirements, the selection of an appropriate salt of the active pharmaceutical ingredient involves a combination of observation, experience and analysis of the structural characteristics of the active ingredient.
After selecting and preparing perhaps several potential candidates (different salts of the drug substance) for initial screening, forced degradation studies and analytical methodology development ensues. Recall that the forced degradation studies are the first steps in evaluating the stability of the selected candidates and have the purpose of deliberately degrading the material to a sufficient extent to observe degradation impurities. This activity further serves the analytical method development effort to identify techniques useful for observing the impurities without interfering with a quantitative measurement of the salt candidate. The analytical techniques employed are inherently chromatographic methodologies (e.g. HPLC, MPLC, GC, TLC) capable of separating complex mixtures into their components. After the initial degradation study, one or more salt candidates may remain suitable for further development.
As a further complication, the initial degradation studies and subsequent stability testing may be complicated by the selected salt candidates' ability to exhibit polymorphism. This property of a compound is its ability to solidify in different crystal structures called polymorphs. Indeed, for a drug substance that exhibits polymorphism, different situations may exist: the material may solidify and be isolated from the reaction as 1) an amorphous solid; 2) a single polymorph may be obtained, or 3) a mixture of polymorphs and 4) combinations of the previous three possibilities. Therefore it is important, when polymorphism is suspected, to deliberately attempt to prepare, isolate and characterize the different polymorphs by techniques sufficient to differentiate between amorphous material and individual polymorphs or their mixtures. Often differential scanning calorimetry (DSC), infrared spectrophotometric analysis, particularly Fourier Transform infrared spectroscopy (FTIR), and powder X-ray diffraction (PXRD) are employed to identify or monitor the creation of polymorphs.
API salts and polymorphs often exhibit different solubility characteristics, for instance rate of dissolution with a pH dependence, and therefore yield a different pharmacokinetic profile and/or therapeutic efficacy. Sometimes, a given drug product formulation expertise or technology can dominate any biological effects the API salt and/or polymorph present. Conversely, drug product formulation and the resulting mechanical properties of a tablet, capsule or bead can be dominated by the physical behavior of the API salt and/or its particular crystal structure. It is not unusual that difficult trade-offs must be made between the ease of manufacture of the drug product and the pharmacokinetics desired.
Concurrent to the pharmacokinetic response desired from formulation techniques, the formulator must address and accommodate the characteristics of the API salt to achieve robust manufacturing processes for the drug product. For instance, the mechanical properties of tablets are influenced by the API salt's physical (and sometimes chemical) characteristics. API salts are often milled to specific particle size ranges to achieve a host of desired features, including but not limited to, blend uniformity of the formulation and enhanced bioavailability (larger surface area available to aid is solubility of moderately insoluble API salts). Tablet mechanical properties, such as hardness, friability, compressive strength, resistance to abrasion, dissolution, and the like can all be impacted by the API salt's physical characteristics. While this example is provided for solid oral dose formulations, other delivery methodologies include but are not limited to injection (solution or suspension), transdermal patches, inhalation devices, and the like, each have their mechanical delivery requirements to implement and deliver a chemical dosage to humans. The formulator often has a difficult task in simultaneously achieving robust manufacturing formulations and expected pharmacokinetic responses. Additionally, the formulator must demonstrate the delivery mechanism and the drug product formulation, combined, have an acceptable stability profile. An interesting complication to these requirements is encountered more frequently as API development and drug discovery has advanced to provide highly potent APIs, and where chemically available, API salts. The overall therapeutic effectiveness of these new drugs is radically increasing and often, the required per unit dosage is very small. It poses significant manufacturing difficulties to weigh or otherwise measure very small quantities of extremely potent drug substances and to achieve formulations that have robust manufacturing processes, with homogenous blend uniformity and that statistically provide a discrete unit dosage per delivery mechanism (e.g. same dosage per tablet).
The prior art indicates significant effort in addressing the stability deficiencies of the thyroid hormones in formulated pharmaceutical compositions. Essentially, two approaches are undertaken, a) improve the stability of the drug substance used in the formulation, or b) impart stability to the drug substance by formulation of the drug product in which the thyroid hormone is used. The former approach is illustrated in U.S. Pat. No. 6,627,660 [Piccariello, et al.], the disclosure of which is totally incorporated herein by reference, discloses dialkylphosphinate protecting groups for the phenolic hydroxyl moiety of thyroxine compounds that prevents a proposed decomposition pathway from occurring. It is suggested that the protecting group prevents the spontaneous tautomerization of T4 that ultimately leads to its decomposition to diiodotyrosine (DIT) and iodoquinone.
Alternatively, several approaches to improving thyroid hormone stability are illustrated in the following patents ostensibly by mechanisms involving the encapsulation of the hormone(s) into a stabilized matrix form, or by providing a common ion effect to eliminate decomposition pathways involving the aryl iodine substitutions. U.S. Pat. No. 6,555,591 [Franz, et al.], the disclosure of which is totally incorporated herein by reference, discloses stabilized pharmaceutical compositions that by formulation methodology using microcrystalline cellulose particles, improves the stability of the thyroid hormone drugs, levothyroxine sodium and liothyronine sodium.
U.S. Pat. No. 6,555,581 B1 [Franz, et al.], the disclosure of which is totally incorporated herein by reference, discloses levothyroxine (T4) and liothyronine (T3) pharmaceutical compositions and the associated methods for preparing immediate release and stabilized formulations.
Similarly, U.S. Pat. No. 6,491,946 B1 [Schreder et al.], the disclosure of which is totally incorporated herein by reference, discloses a pharmaceutical preparation of levothyroxine absent antioxidants and further auxiliaries and processes for preparing same.
U.S. Pat. No. 6,399,101 [Frontanes, et al.], the disclosure of which is totally incorporated herein by reference, discloses stabilized pharmaceutical compositions that by formulation methodology using silicified microcrystalline cellulose, improves the stability of the thyroid hormone drug, levothyroxine sodium.
U.S. Pat. No. 6,190,696 [Groenewoud] the disclosure of which is totally incorporated herein by reference, discloses stabilized pharmaceutical compositions that by formulation methodology using one or more iodine salts or iodine donor compounds, improves the shelf-life stability of thyroxine medications and their combinations.
U.S. Pat. No. 6,056,975 [Mitra, et al.], the disclosure of which is totally incorporated herein by reference, discloses stabilized pharmaceutical compositions that by formulation methodology using a proscribed carbohydrate possessing the characteristic property of a water soluble glucose polymer, improves the stability of the thyroid hormone drug, levothyroxine sodium.
U.S. Pat. No. 5,955,105 [Mitra, et al.], the disclosure of which is totally incorporated herein by reference, discloses stabilized pharmaceutical compositions that by formulation methodology using a proscribed carbohydrate possessing the characteristic property of a water soluble glucose polymer, and a soluble or insoluble cellulose polymer, improves the stability of the thyroid hormone drug, levothyroxine sodium.
U.S. Pat. No. 5,635,209 [Groenewoud, et al.], the disclosure of which is totally incorporated herein by reference, discloses a stabilized pharmaceutical composition that by formulation methodology uses potassium iodide, acting as a stabilizing excipient, improves the stability of the thyroid hormone drug levothyroxine sodium.
It is of some historical interest that the pamoate salts of a variety of active pharmaceutical ingredients have received attention, noting that an embonate salt is identical to a pamoate salt. In the following cited literature, the pamoate was apparently chosen a) for converting a liquid active pharmaceutical ingredient into a solid, b) for eliminating the bitter taste associated with many active pharmaceutical ingredients, or c) as a process for isolating and then chemically characterizing otherwise difficult to delineate alkaloids or active pharmaceutical ingredients. For instance, U.S. Pat. No. 5,232,919 [Scheffler, et al.], the disclosure of which is totally incorporated herein by reference, discloses azelastine embonate and pharmaceutical formulations/compositions which contain it; said embonate salt to eliminate the bitter taste of azelastine alone.
Further, the French Patent 1,461,407 [Saias, et al.], the disclosure of which is totally incorporated herein by reference, discloses a process for the preparation of amine pamoates where the amine component includes piperazine, promethazine, papaverine, pholocodine, codeine, noracotine and chlorpheniramine.
The United Kingdom Patent Specification [295,656, Carpmaels & Ransford, agents for applicants] the disclosure of which is totally incorporated herein by reference, discloses a process for the manufacture of difficulty soluble salts of organic bases and alkaloids. The disclosure further indicates the process for manufacture provides sparingly soluble and tasteless salts of organic nitrogenous basic compounds including alkaloids.
U.S. Pat. No. 3,502,661 [Kasubick, et al.], the disclosure of which is totally incorporated herein by reference, discloses a process for the preparation of variously substituted pyridinium and imidazolines along with their acid addition salts. Some examples indicate pamoate salts were prepared for select organic bases.
U.S. Pat. No. 2,925,417 [Elslager, et al.], the disclosure of which is totally incorporated herein by reference, discloses quinolinium salts of pamoic acid and a process for their manufacture.
Lastly, the following cited literature indicates the incorporation of pamoate salts in pharmaceutical formulations for providing the controlled release of water insoluble polypeptides or the oil soluble azelastine. Hence, U.S. Pat. No. 5,776,885 [Orsolini, et al.], the disclosure of which is totally incorporated herein by reference, discloses a pharmaceutical composition for the sustained and controlled release of water insoluble polypeptides whereby the therapeutically active peptide is in the form of its pamoate, tannate or stearate salt.
U.S. Pat. No. 5,445,832 [Orsolini, et al.], the disclosure of which is totally incorporated herein by reference, discloses a process for the preparation of microspheres made of a biodegradable polymeric material whereby a water soluble peptide or peptide salt is converted into a corresponding water-insoluble peptide salt selected from pamoates, stearates or palmitates of the said peptide.
U.S. Pat. No. 5,439,688 [Orsolini, et al.], the disclosure of which is totally incorporated herein by reference, discloses a process for preparing a pharmaceutical composition in the form of microparticles designed for the controlled release of a drug that includes a biodegradable polymer and where the active ingredient can be selected from a group of possible salts, one being a pamoate.
U.S. Pat. No. 5,271,946 [Hettche] the disclosure of which is totally incorporated herein by reference, discloses a controlled release azelastine containing pharmaceutical composition whereby azelastine is incorporated into the formulation as its pamoate or other pharmaceutically active salt.
U.S. Pat. No. 5,225,205 [Orsolini, et al.], the disclosure of which is totally incorporated herein by reference, discloses a pharmaceutical composition in the form of microparticles; the formulation consisting of a peptide as its pamoate, tannate, stearate or palmitate salt; the formulation to provide a controlled release, pharmaceutical composition for the prolonged release of a medicamentous substance.
Formulated drug products containing thyroid hormones have received intense scrutiny from the US Food and Drug Administration (FDA) over the past decade. In particular, the FDA's responsibility for protecting the US population by reviewing and assuring that only safe and efficacious drug products are commercially available, has led the FDA to reassess the approval process of the thyroid hormones, specifically levothyroxine containing products. Synthroid is a commercial drug product containing levothyroxine and has been available for US consumption for decades. With increased reports on the instability and difficulty in obtaining efficacious dosage forms, the FDA instituted a requirement that Synthroid be subjected to the current regulatory approval process as if it were a new drug. The FDA announced on Aug. 14, 1997 via the Federal Register (62 FR 43535) that levothyroxine sodium in oral dosage presentations constitute “new drugs” and that the continued marketing of these products must comply with the new drug application (NDA) approval process. The intention was an NDA submission would necessitate final dose manufacturers to perform the statistical experimentation required to demonstrate long-term stability of the drug product, a uniform and consistent dosage per tablet, and consequently, that patients would receive the proper therapeutic dosage of a life-saving drug. The FDA mandate has created considerable market “disturbance” and essentially because of regulatory pressures Synthroid was ultimately purchased and transferred from one company to another. The new owners of the drug product filed an NDA and received the FDA's approval. Excerpted verbatim from the FDA's “Review and Evaluation of Pharmacology/Toxicology Data” for the new drug application NDA 21-210 and in regard to unapproved products is the following:
“One problem with currently marketed formulations is a lack of stability and batch to batch reliability.”
Despite gaining regulatory acceptance via the New Drug Application, the drug product and the drug substance have inherent technical challenges primarily due to the instability of the API. The commercial aspects for Synthroid and related thyroid hormone products to supplement or replace Synthroid are in excess of $500 million US dollars. Hence, the motivation to correct and improve deficiencies in the current products and their precursor APIs, albeit in addition to those already addressed by the FDA's indomitable spirit for protecting the public, is substantial.
On Oct. 3, 2007, the U.S. Food and Drug Administration released the following notice: “FDA Acts to Ensure Thyroid Drugs Don't Lose Potency Before Expiration Date”. As such, the FDA has issued letters to all new drug application (NDA) and abbreviated new drug application (ANDA) holders requiring that they change the product specification on levothyroxine sodium products to meet a 95% to 105% potency specification throughout the product's labeled shelf-life. Formerly, the accepted specification was 90-110%. The new specification is a challenging goal to which manufacturers of levothyroxine products must submit a Supplement to their (A)NDA within eighteen months and with the expectation the revised potency specification implemented into commercial operations within twenty-four months.